Obesity is a condition wherein fat is excessively accumulated in a body (Non-Patent Document 1), and may lead to hyperlipidemia, hypertriglycemia, lipid metabolism disorder, fatty liver, diabetes, hypertension, arteriosclerosis, cerebrovascular disorder, coronary artery disease, dyspnoea, lumbago, gonarthrosis, and the like. Among obesity, those having these diseases or those which may possibly cause these diseases in the future are defined as adiposity, and regarded as one of diseases.
DGAT is an enzyme catalyzing a reaction from diacylglyerol to TG, which reaction is the final stage of triacylglycerol (TG) synthesis, and it is known that DGAT has two kinds of subtypes, DGAT1 and DGAT2. Among these, DGAT1 is known to exist in liver, skeletal muscle, adipocytes, and the like, and is involved in the TG synthesis in each tissue (Non-Patent Document 2).
Further, when TG is absorbed in the small intestine, TG is decomposed by pancreatic lipase in the lumen of the small intestine to fatty acid and mono acylglycerol, then incorporated into small intestinal epithelial cells, and absorbed after it is resynthesized to TG in the epithelial cells, and it has been known that DGAT1 is also involved in the final stage of TG resynthesis in the small intestinal epithelial cells (Non-Patent Document 3).
Therefore, a compound which inhibits DGAT1 is expected to improve the pathology of obesity since it not only inhibits TG synthesis in adipocyte, liver and the like by inhibiting the final step of TG synthesis but also suppresses the TG absorption in small intestines by suppressing the TG resynthesis in small intestine (Non-Patent Document 4).
Further, a theory that the accumulation of TG in liver, skeletal muscle, and the like (ectopic fat accumulation) is a cause of insulin resistance in type 2 diabetes mellitus accompanying obesity has been widely accepted, and a compound which inhibits DGAT1 is expected to improve the insulin sensitivity and has the therapeutic effect on type 2 diabetes mellitus by alleviating the ectopic fat accumulation (Non-Patent Document 4). Furthermore, in a mouse deleted in DGAT1 by genetic manipulation (DGAT1 knockout mouse), it was reported that the improvement in the insulin sensitivity was observed as compared with a wild type mouse (Non-Patent Document 5). It was recently reported that a compound which inhibits DGAT1 stimulates the action of glucagon-like peptide-1 (GLP-1) and a protein which causes anorexia (Non-Patent Document 6).
As a compound having a continuous aromatic ring structure, the following has been known. For example, in Patent Document 1, (2S)-2-[4′-(1-benzyl-1H-benzimidazole-2-yl)-biphenyl-4-yloxy]-3-phenyl-propionic acid (Example 70) and the like are disclosed as a compound which inhibits protein-tyrosine phosphatase (PTPases) and is useful for the treatment of insulin resistance accompanying obesity, glucose intolerance, diabetes, hypertension, or ischemic disease.
In Patent Document 2, as a compound having an inhibitory activity against protein-tyrosine phosphatase 1B (PTP-1B) which is useful for the treatment of type 2 diabetes mellitus, 2-benzyl-4-[4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yl]-4-oxo-butyric acid (Example 1), ({4′-(3-benzylamino)imidazo[1,2-a]pyridin-2-yl)biphenyl-4-yl}oxy)(phenyl)acetic acid, {[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl) acetic acid (Example 3), and the like are disclosed.
In Patent Document 3, Patent Document 4 and Patent Document 5, a compound having an inhibitory activity against Factor VIIa, Factor IXa, Factor Xa, and/or Factor XIa which has a structure wherein biphenyl and nitrogen-containing fused heterocyclic ring are bonded is disclosed. However, the chemical structure is restricted to those having a structure wherein the nitrogen-containing fused heterocyclic ring is bonded at the 3-position of the biphenyl.
In Patent Document 6, 2-[[2′-(5-phenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]acetic acid (Example 46) and the like as a compound having the therapeutic effect on obesity and diabetes by inhibiting adipocyte fatty acid-binding protein (aP2) are disclosed.
In Non-Patent Document 7, 2-[[2′-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl) [1,1′-biphenyl]-3-yl]oxy]acetic acid, 2-[[2′-(4,5-diphenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]acetic acid, and the like as a compound which binds to adipocyte fatty acid-binding protein (aFABP) are reported.
As another compound having a continuous ring structure, those in, for example, Patent Documents 7 to 14 and Non-Patent Document 8 are known.
Also, as a compound having DGAT1 inhibitory activity, for example, heteroarylbenzene derivatives (Patent Document 15), bicyclic heterocyclic compounds (Patent Document 16), triazolopyridine derivatives (Patent Document 17), imidazole derivatives (Patent Documents 18 to 20), spiro-ring compounds (Patent Document 21), and biaryl compounds (Patent Document 22) are known.